Compounds which inhibit HMG-CoA reductase, the enzyme controlling the rate-limiting step in cholesterol biosynthesis, are assuming an important role in the management of certain forms of hyperlipidemia. Lovastatin, disclosed in U.S. Pat. No. 4,231,938, has been approved for use in the treatment of primary hypercholesterolemia, a disease characterized by normal serum triglyceride levels and elevated serum levels of low density lipoprotein (LDL) cholesterol and total cholesterol. In several large clinical studies, lovastatin was found to decrease plasma LDL and total cholesterol concentrations 25% to 40% while causing small but significant increases (up to 10%) in high density lipoprotein (HDL) cholesterol concentration. When compared with cholestyramine and probucol, two drugs used in the treatment of primary hypercholesterolemia, lovastatin reduced LDL cholesterol levels to a significantly greater extent. In addition, combined administration of lovastatin with other hypolipidemic agents was found to potentiate their effects on LDL and total cholesterol concentrations.
The biochemical target for lovastatin is HMG-CoA reductase, the enzyme which catalyzes the reduction of HMG-CoA to mevalonic acid. Lovastatin, in its open dihydroxy acid form, is a reversible, competitive inhibitor of the enzyme. A number of compounds structurally related to lovastatin have been shown to be inhibitors of HMG-CoA reductase. These include simvastatin (U.S. Pat. No. 4,444,784 and related compounds disclosed in U.S. Pat. No. 4,444,784). Sankyo has reported a related compound, pravastatin (U.S. Pat. No. 4,346,227). Sandoz has reported a number of HMG-CoA reductase inhibitors: indoles (U.S. Pat. No. 4,739,073), pyrazoles (U.S. Pat. No. 4,613,610), imidazoles (U.S. Pat. No. 4,808,607), and pyrazolopyridines (U.S. Pat. No. 4,822,799). Merck disclosed biphenyl-containing inhibitors in U.S. Pat. No. 4,375,475. Hoechst AG disclosed non-heterocyclic HMG-CoA reductase inhibitors in Tetrahedron Letters, 1988, 29, 929. Bristol-Myers reported tetrazole-containing compounds in UK Patent 2,202,846. Acylpyrroles are reported in U.S. Pat. No. 4,681,893 by Warner-Lambert. Warner-Lambert also disclosed pyrimidines in U.S. Pat. No. 4,868,185 and quinolines in U.S. Pat. No. 4,761,419. Bayer AG reported tri-arylpyrroles in European Patent 287,890. Rorer reported aryl-cycloalkene and aryl-cycloalkadiene inhibitors in U.S. Pat. Nos. 4,892,884 and 4,900,754. Squibb reported a number of potent compounds based on a variety of heterocycles in Journal of Medicinal Chemistry, 1990, 33, 2852. Finally, Upjohn disclosed in WO 867,357 an anti-inflammatory, anti-allergic compound generically described as cyclopentapyrazole.
The compounds of the present invention are structurally different from the known compounds and have been shown to be potent inhibitors of HMG-CoA reductase and cholesterol biosynthesis.